Myxoma Virus Induces Ligand Independent Extrinsic Apoptosis in Human Myeloma Cells.

Abstract

Multiple myeloma is a clonal malignancy of plasma B cells. Although recent advances have improved overall prognosis, virtually all myeloma patients still succumb to relapsing disease. Therefore, novel therapies to treat this disease remain urgently needed. We have recently shown that treatment of human multiple myeloma cells with an oncolytic virus known as myxoma results in rapid cell death even in the absence of viral replication; however, the specific mechanisms and pathways involved remain unknown. To determine how myxoma virus eliminates human multiple myeloma cells, we queried the apoptotic pathways that were activated after viral infection using immunoblot analysis and other cell biology approaches. Our results indicate that myxoma virus infection initiates apoptosis in multiple myeloma cells through activation of the extrinsic initiator caspase-8. Caspase-8 activation subsequently results in cleavage of BH3 interacting-domain death agonist and loss of mitochondrial membrane potential causing secondary activation of caspase-9. Activation of caspase-8 appears to be independent of extrinsic death ligands and instead correlates with depletion of cellular inhibitors of apoptosis. We hypothesize that this depletion results from virally mediated host-protein shutoff because a myxoma construct that overexpresses the viral decapping enzymes displays improved oncolytic potential. Taken together, these results suggest that myxoma virus eliminates human multiple myeloma cells through a pathway unique to oncolytic poxviruses, making it an excellent therapeutic option for the treatment of relapsed or refractory patients.